Variability in soil properties influencing pigeonpea ( ) yield: a multivariate statistical analysis.

The aim of the study was to reveal the variability in soil properties influencing pigeonpea ( ) seed yield under semi-arid rainfed condition. Soils were initially classified into series level and further these series were divided into soil-phase units. For two site years , 2018-19 and 2019-20, surface soil samples from each soil-phase unit were collected before sowing of pigeonpea and subsequently crop growth parameters at critical stages were recorded.

Treatment scheduling effects on the evolution of drug resistance in heterogeneous cancer cell populations.

The effect of scheduling of targeted therapy combinations on drug resistance is underexplored in triple-negative breast cancer (TNBC). TNBC constitutes heterogeneous cancer cell populations the composition of which can change dynamically during treatment resulting in the selection of resistant clones with a fitness advantage. We evaluated crizotinib (ALK/MET inhibitor) and navitoclax (ABT-263; Bcl-2/Bcl-xL inhibitor) combinations in a large design consisting of 696 two-cycle sequential and concomitant treatment regimens with varying treatment dose, duration, and drug holiday length over a 26-day period in MDA-MB-231 TNBC cells and found that patterns of resistance depend on the schedule and sequence in which the drugs are given.

Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers.

Background: Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases.

Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells.

Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells.

Analysis of Pre- and Posttreatment Tissues from the SWOG S0800 Trial Reveals an Effect of Neoadjuvant Chemotherapy on the Breast Cancer Genome.

Purpose: We performed whole-exome sequencing (WES) of pre- and posttreatment cancer tissues to assess the somatic mutation landscape of tumors before and after neoadjuvant taxane and anthracycline chemotherapy with or without bevacizumab.

Experimental Design: Twenty-nine pretreatment biopsies from the SWOG S0800 trial were subjected to WES to identify mutational patterns associated with response to neoadjuvant chemotherapy. Nine matching samples with residual cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy.

Identification and Validation of a Novel Biologics Target in Triple Negative Breast Cancer.

The goal of this study was to identify a novel target for antibody-drug conjugate (ADC) development in triple negative breast cancer (TNBC), which has limited treatment options, using gene expression datasets and in vitro siRNA/CRISPR and in vivo functional assays. We analyzed 4467 breast cancers and identified GABRP as top expressed gene in TNBC with low expression in most normal tissues. GABRP protein was localized to cell membrane with broad range of receptors/cell (815-53,714) and expressed by nearly half of breast cancers tissues.

Reliability of Whole-Exome Sequencing for Assessing Intratumor Genetic Heterogeneity.

Multi-region sequencing is used to detect intratumor genetic heterogeneity (ITGH) in tumors. To assess whether genuine ITGH can be distinguished from sequencing artifacts, we performed whole-exome sequencing (WES) on three anatomically distinct regions of the same tumor with technical replicates to estimate technical noise. Somatic variants were detected with three different WES pipelines and subsequently validated by high-depth amplicon sequencing.

Immunological differences between primary and metastatic breast cancer.

Background: Little is known about how the immune microenvironment of breast cancer evolves during disease progression.

Patients And Methods: We compared tumor infiltrating lymphocyte (TIL) count, programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry and mRNA levels of 730 immune-related genes using Nanostring technology in primary and metastatic cancer samples.

Results: TIL counts and PD-L1 positivity were significantly lower in metastases.

Increased epigenetic age in normal breast tissue from luminal breast cancer patients.

Background: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes.

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.

Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.

Methods And Findings: We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts.

Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer.

The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer. HRD scores, BRCA mutation status, and promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas.

miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents.

Characterization of DNA variants in the human kinome in breast cancer.

Kinases play a key role in cancer biology, and serve as potential clinically useful targets for designing cancer therapies. We examined nucleic acid variations in the human kinome and several known cancer-related genes in breast cancer. DNA was extracted from fine needle biopsies of 73 primary breast cancers and 19 metastatic lesions.

Overexpression of ERBB4 JM-a CYT-1 and CYT-2 isoforms in transgenic mice reveals isoform-specific roles in mammary gland development and carcinogenesis.

Introduction: Human Epidermal Growth Factor Receptor (ERBB4/HER4) belongs to the Epidermal Growth Factor receptor/ERBB family of receptor tyrosine kinases. While ERBB1, ERBB2 and ERBB3 are often overexpressed or activated in breast cancer, and are oncogenic, the role of ERBB4 in breast cancer is uncertain. Some studies suggest a tumor suppressor role of ERBB4, while other reports suggest an oncogenic potential.

Metabolic isoenzyme shifts in cancer as potential novel therapeutic targets.

The functional redundancy of metabolic enzyme expression may present a new strategy for developing targeted therapies in cancer. To satisfy the increased metabolic demand required during neoplastic transformations and proliferation, cancer cells may rely on additional isoforms of a metabolic enzyme to satisfy the increased demand for metabolic precursors, which could subsequently render cancer cells more vulnerable to isoform-specific inhibitors. In this review, we provide a survey of common isoenzyme shifts that have been reported to be important in cancer metabolism and link those to metabolic pathways that currently have drugs in various stages of development.

Statistical measures of transcriptional diversity capture genomic heterogeneity of cancer.

Background: Molecular heterogeneity of tumors suggests the presence of multiple different subclones that may limit response to targeted therapies and contribute to acquisition of drug resistance, but its quantification has remained challenging.

Results: We performed simulations to evaluate statistical measures that best capture the molecular diversity within a group of tumors for either continuous (gene expression) or discrete (mutations, copy number alterations) molecular data. Dispersion based metrics in the principal component space best captured the underlying heterogeneity.

Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells.

Unlabelled: Associations of ErbB4 (ERBB4/HER4), the fourth member of the EGFR family, with cancer are variable, possibly as a result of structural diversity of this receptor. There are multiple structural isoforms of ERBB4 arising by alternative mRNA splicing, and a subset undergo proteolysis that releases membrane-anchored and soluble isoforms that associate with transcription factors and coregulators to modulate transcription. To compare the differential and common signaling activities of full-length (FL) and soluble intracellular isoforms of ERBB4, four JM-a isoforms (FL and soluble intracellular domain (ICD) CYT-1 and CYT-2) were expressed in isogenic MCF10A cells and their biologic activities were analyzed.

Global gene expression changes induced by prolonged cold ischemic stress and preservation method of breast cancer tissue.

Background: Tissue handling can alter global gene expression potentially affecting the analytical performance of genomic signatures, but such effects have not been systematically evaluated.

Methods: Tissue samples from 11 previously untreated breast tumors were minced and aliquots were either snap frozen or placed in RNAlater immediately or after 20, 40, 60, 120 or 180 min at room temperature. RNA was profiled on Affymetrix HG-U133A arrays.

Tocotrienol combination therapy results in synergistic anticancer response.

Vitamin E represents a family of compounds that is divided into two subgroups called tocopherols and tocotrienols, which act as important antioxidants that regulate peroxidation reactions and control free-radical production within the body. However, many of the biological effects of vitamin E are mediated independently of its antioxidant activity. Although tocopherols and tocotrienols have the same basic chemical structure characterized by a long phytyl chain attached to a chromane ring, only tocotrienols display potent anticancer activity, by modulating multiple intracellular signaling pathways associated with tumor cell proliferation and survival, and combination therapy with other chemotherapeutic agents result in a synergistic anticancer response.

Synthesis of fluorescent analogues of the anticancer natural products 4-hydroxyphenylmethylene hydantoin and delta-tocotrienol.

4-Hydroxyphenylmethylene hydantoin (PMH, 1), isolated from the Red Sea sponge Hemimycale arabica, and delta-tocotrienol (3), isolated from the tocotrienol-rich fraction of palm oil, are important antimetastatic and antiproliferative natural products that proved effective against metastatic prostate and breast cancers, respectively. New fluorescent derivatives of PMH (2) and delta-tocotrienol (4) were synthesized by Steglich esterification. Both 2 and 4 retained good anti-migratory and antiproliferative activities, respectively.

Redox-silent tocotrienol esters as breast cancer proliferation and migration inhibitors.

Tocotrienols are vitamin E members with potent antiproliferative activity against preneoplastic and neoplastic mammary epithelial cells with little or no effect on normal cell growth or functions. However, physicochemical and pharmacokinetic properties greatly limit their use as therapeutic agents. Tocotrienols' chemical instability, poor water solubility, NPC1L1-mediated transport, and rapid metabolism are examples of such obstacles which hinder the therapeutic use of these valuable natural products.

Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells.

Background: Heterodimer cooperation between ErbB receptors has limited clinical usefulness of receptor tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib in the treatment of cancer. However, combination treatment of TKIs with gamma-tocotrienol targets multiple ErbB receptors and significantly inhibit +SA murine mammary tumor cell growth.

Materials And Methods: Cell proliferation was determined by tetrazolium (MTT) assay and immunofluorescent Ki-67 staining.